MYCN amplification regulates DNA-PK expression and resistance to radiation therapy in neuroblastoma (Radiation Medicine and Markey Cancer Center Collaborative Bench to Bedside pilot) (RPA Pilot / Seed Project)

"Neuroblastoma (NB) is the most common extracranial solid tumor in children and
accounts for 12% of all pediatric cancer deaths. Targeted radiotherapy provides means of delivering radiation therapy with a high therapeutic index to organs affected by NBs metastasis. However, limited clinical
responses or resistance to radiation therapy were observed highlighting needs to determine subsets of neuroblastomas responsive to radiotherapy, and to develop combination treatment strategy with
radiosensitizers. The mechanism of primary and acquired radiation resistance to radionuclide therapy in NBs is poorly understood and the contribution of DNA-PK, a key regulator of DNA double-strand breakage repairs, in radiation resistance is not known. Therefore, this project will examine MYCN amplification and its control of DNA-PK expression as the mechanism of radiation resistance in NB tumors, and the therapeutic potential of DNA-PK inhibition to overcome resistance to radiation therapy in MYCN-amplified tumors. Significance to science and “bench to bedside” translational potential. The ultimate translational goal of our collaborative and multidisciplinary proposal is to develop an effective, less toxic approach to enhance efficiency of targeted radiotherapy in patients with MYCN-amplified NBs. Therefore, in Aim 1, we will elucidate the biological mechanism of DNA-PK regulation during DNA damage repair in NB. In Aim 2, we will evaluate the translational potential of low-toxicity DNA-PK inhibitor peposertib in combination with radiotherapy in NB liver metastasis."